Plasma PCSK9 levels are significantly modified by statins and fibrates in humans.
Plasma PCSK9 levels are significantly modified by statins and fibrates in humans.
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DOI：
10.1186/1476-511x-7-22
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发表时间：
2008-06-11
影响因子：
4.5
通讯作者：
Chrétien M
中科院分区：
文献类型：
--
作者：
Mayne J;Dewpura T;Raymond A;Cousins M;Chaplin A;Lahey KA;Lahaye SA;Mbikay M;Ooi TC;Chrétien M
前蛋白转化酶枯草杆菌蛋白酶样 9 (PCSK9) 是一种分泌型糖蛋白，受胆固醇状态转录调节。它通过负向调节低密度脂蛋白受体 (LDLR) 水平来调节循环低密度脂蛋白胆固醇 (LDLC) 水平。导致“功能获得”的 PCSK9 变异与常染色体显性高胆固醇血症有关，而携带“功能丧失”PCSK9 变异的个体则可显着预防冠状动脉疾病。 PCSK9在人体血浆中循环，我们之前报道男性血浆PCSK9与总胆固醇和LDLC呈正相关。在此，我们报告了两种脂质调节疗法（即他汀类药物和贝特类药物）对人类受试者 PCSK9 血浆水平的影响。我们还使用免疫沉淀和免疫印迹分析记录了它们对人肝细胞系 HepG2 中内源性 PCSK9 和 LDLR 表达的影响。非诺贝特或吉非贝齐（纤维酸衍生物）治疗后血浆 PCSK9 的变化与 LDLC 水平的变化呈负相关（r = -0.558，p = 0.013）。阿托伐他汀给药（HMGCoA还原酶抑制剂）显着增加血浆PCSK9（7.40％，p = 0.033），并且这些变化与LDLC水平的变化呈负相关（r = -0.393，p = 0.012）。对 HepG2 细胞响应他汀类药物和贝特类药物的内源性 PCSK9 和 LDLR 表达的免疫印迹分析表明，辛伐他汀对 LDLR 的上调程度比 PCSK9 更高（10 μM 时分别为 2.6 倍 vs 1.5 倍），而非诺贝特均未引起任何变化。这些结果表明，体内（1）他汀类药物直接增加 PCSK9 表达，而（2）贝特类药物通过调节胆固醇水平间接影响 PCSK9 表达，（3）这些疗法可以通过与 PCSK9 抑制剂组合得到改善，构成一种新型高胆固醇血症疗法，因为两种疗法均显着上调 PCSK9。
Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men. Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6× vs 1.5×, respectively at 10 μM), while fenofibrate did not induce changes in either. These results suggest that in vivo (1) statins directly increase PCSK9 expression while (2) fibrates affect PCSK9 expression indirectly through its modulation of cholesterol levels and (3) that these therapies could be improved by combination with a PCSK9 inhibitor, constituting a novel hypercholesterolemic therapy, since PCSK9 was significantly upregulated by both treatments.